Peripheral Aromatic L-amino Acid Decarboxylase Research Articles

Evaluation of 3-l- and 3-d-[18F]Fluorophenylalanines as PET Tracers for Tumor Imaging.

Simple SummaryThe early detection and treatment of malignant brain tumors can significantly improve the survival time and life quality of affected patients. Whereas positron emission tomography (PET) with O-(2-[18F]fluoroethyl)tyrosine ([18F]FET) offers improved diagnostic accuracy compared to other imaging methods, there is still a need for PET tracers with better tumor-specificity. A higher protein incorporation rate, as well as a higher affinity for the amino acid transporter LAT1, could provide probes with superior image quality compared to [18F]FET. The aim of the present study was a preclinical evaluation of the two enantiomeric phenylalanine (Phe) analogues, 3-l- and 3-d-[18F]fluorophenylalanine ([18F]FPhes), as possible alternatives to [18F]FET. Based on promising in vitro evaluation results, the radiolabeled amino acids were studied in vivo in two subcutaneous and one orthotopic rodent tumor xenograft models using µPET. The results show that 3-l- and 3-d-[18F]FPhe enable high-quality visualization of tumors with certain advantages over [18F]FET, making them promising candidates for further preclinical and clinical evaluations. Purpose: The preclinical evaluation of 3-l- and 3-d-[18F]FPhe in comparison to [18F]FET, an established tracer for tumor imaging. Methods: In vitro studies were conducted with MCF-7, PC-3, and U87 MG human tumor cell lines. In vivo µPET studies were conducted in healthy rats with/without the inhibition of peripheral aromatic l-amino acid decarboxylase by benserazide pretreatment (n = 3 each), in mice bearing subcutaneous MCF-7 or PC-3 tumor xenografts (n = 10), and in rats bearing orthotopic U87 MG tumor xenografts (n = 14). Tracer accumulation was quantified by SUVmax, SUVmean and tumor-to-brain ratios (TBrR). Results: The uptake of 3-l-[18F]FPhe in MCF-7 and PC-3 cells was significantly higher relative to [18F]FET. The uptake of all three tracers was significantly reduced by the suppression of amino acid transport systems L or ASC. 3-l-[18F]FPhe but not 3-d-[18F]FPhe exhibited protein incorporation. In benserazide-treated healthy rats, brain uptake after 42–120 min was significantly higher for 3-d-[18F]FPhe vs. 3-l-[18F]FPhe. [18F]FET showed significantly higher uptake into subcutaneous MCF-7 tumors (52–60 min p.i.), while early uptake into orthotopic U87 MG tumors was significantly higher for 3-l-[18F]FPhe (SUVmax: 3-l-[18F]FPhe, 107.6 ± 11.3; 3-d-[18F]FPhe, 86.0 ± 4.3; [18F]FET, 90.2 ± 7.7). Increased tumoral expression of LAT1 and ASCT2 was confirmed immunohistologically. Conclusion: Both novel tracers enable accurate tumor delineation with an imaging quality comparable to [18F]FET.

Peripheral decarboxylase inhibitors paradoxically induce aromatic L-amino acid decarboxylase

Peripheral decarboxylase inhibitors (PDIs) prevent conversion of levodopa to dopamine in the blood by the enzyme aromatic L-amino acid decarboxylase (AADC). Alterations in enzyme activity may contribute to the required higher dosages of levodopa observed in many patients with Parkinson’s disease. We evaluated the effect of levodopa/PDI use on serum AADC enzyme activity. Serum AADC enzyme activity was evaluated in three independent cohorts of patients with Parkinson’s disease or parkinsonism (n = 301) and compared between patients on levodopa/PDI vs. patients not on this medication. AADC enzyme activity was elevated in 62% of patients on levodopa/PDI treatment, compared to 19% of patients not on levodopa/PDI (median 90 mU/L vs. 50 mU/L, p < 0.001). Patients with elevated AADC activity had longer disease duration and higher doses of levodopa/PDI. These findings may implicate that peripheral AADC induction could underlie a waning effect of levodopa, necessitating dose increases to maintain a sustained therapeutic effect.

Nanocarrier for levodopa Parkinson therapeutic drug; comprehensive benserazide analysis

Loss of dopamine-secreting neurons in the midbrain causes Parkinson’s disease. L-DOPA, the precursor to the neurotransmitters dopamine, crosses vast majority of physiological and biochemical barriers that dopamine cannot. But most levodopa is decarboxylated to dopamine before it reaches the brain. This causes to little therapeutic gain with strong peripheral side effects. Benserazide is an irreversible inhibitor of peripheral aromatic L-amino acid decarboxylase that prevents the breakdown of levodopa in the bloodstream. The challenges are to increase the therapeutic efficiency, the bioavailability and decreasing the unfavourable side effects of Levodopa drug. Biocompatible nano-sized drug carriers could address these challenges at molecular level. Thus calculations of drug loading ability of acid-functionalized CNT for the benserazide as a nanodug carrier complex for L-DOPA were performed. In this regard, evaluation of all adsorption features of the most stable conformer of benserazide molecule onto carboxylated carbon nanotube is critical. To determine the minimum energy conformer of benserazide, the molecular structure and conformational analysis of 512 possible conformers have been subjected to first principle quantum mechanical calculations. Our work established a novel and easy-to-make formulation of benserazide/carboxylated CNT conjugate with extremely high drug loading efficiency of Levodopa for Parkinson disease treatment.

Production of Dopamine by Aromatic l-Amino Acid Decarboxylase Cells after Spinal Cord Injury.

Aromatic l-amino acid decarboxylase (AADC) cells are widely distributed in the spinal cord, and their functions are largely unknown. We have previously found that AADC cells in the spinal cord could increase their ability to produce serotonin (5-hydroxytryptamine) from 5-hydroxytryptophan after spinal cord injury (SCI). Because AADC is a common enzyme catalyzing 5-hydroxytryptophan to serotonin and l-3,4-dihydroxyphenylalanine (l-dopa) to dopamine (DA), it seems likely that the ability of AADC cells using l-dopa to synthesize DA is also increased. To prove whether or not this is the case, a similar rat sacral SCI model and a similar experimental paradigm were adopted as that which we had used previously. In the chronic SCI rats (> 45 days), no AADC cells expressed DA if there was no exogenous l-dopa application. However, following administration of a peripheral AADC inhibitor (carbidopa) with or without a monoamine oxidase inhibitor (pargyline) co-application, systemic administration of l-dopa resulted in ∼94% of AADC cells becoming DA-immunopositive in the spinal cord below the lesion, whereas in normal or sham-operated rats none or very few of AADC cells became DA-immunopositive with the same treatment. Using tail electromyography, spontaneous tail muscle activity was increased nearly fivefold over the baseline level. When pretreated with a central AADC inhibitor (NSD-1015), further application of l-dopa failed to increase the motoneuron activity although the expression of DA in the AADC cells was not completely inhibited. These findings demonstrate that AADC cells in the spinal cord below the lesion gain the ability to produce DA from its precursor in response to SCI. This ability also enables the AADC cells to produce 5-HT and trace amines, and likely contributes to the development of hyperexcitability. These results might also be implicated for revealing the pathological mechanisms underlying l-dopa-induced dyskinesia in Parkinson's disease.

Evaluation of 6-11C-Methyl-m-Tyrosine as a PET Probe for Presynaptic Dopaminergic Activity: A Comparison PET Study with β-11C-l-DOPA and 18F-FDOPA in Parkinson Disease Monkeys.

We recently developed a novel PET probe, 6-(11)C-methyl-m-tyrosine ((11)C-6MemTyr), for quantitative imaging of presynaptic dopamine synthesis in the living brain. In the present study, (11)C-6MemTyr was compared with β-(11)C-l-DOPA and 6-(18)F-fluoro-l-dopa ((18)F-FDOPA) in the brains of normal and Parkinson disease (PD) model monkeys (Macaca fascicularis). PD model monkeys were prepared by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration, and (11)C-β-CFT was applied to assess neuronal damage as dopamine transporter (DAT) availability. (11)C-6MemTyr, β-(11)C-l-DOPA, or (18)F-FDOPA was injected with and without carbidopa, a specific inhibitor of peripheral aromatic L-amino acid decarboxylase. In normal and PD monkeys, the dopamine synthesis rates calculated using PET probes were analyzed by the correlation plot with DAT availability in the striatum. In normal monkeys, whole-brain uptake of β-(11)C-l-DOPA and (18)F-FDOPA were significantly increased by carbidopa at the clinical dose of 5 mg/kg by mouth. In contrast, (11)C-6MemTyr was not affected by carbidopa at this dose, and the metabolic constant value of (11)C-6MemTyr in the striatum was significantly higher than those of the other 2 PET probes. Significant reduction of the presynaptic DAT availability in the striatum was detected in MPTP monkeys, and correlation analyses demonstrated that (11)C-6MemTyr could detect dopaminergic damage in the striatum with much more sensitivity than the other PET probes. (11)C-6MemTyr is a potential PET probe for quantitative imaging of presynaptic dopamine activity in the living brain with PET.

In vivo antagonism of the behavioral responses to L-3-,4-dihydroxyphenylalanine by L-3-,4-dihydroxyphenylalanine cyclohexyl ester in conscious rats

To establish the neurotransmitter role(s) of L-3,4-dihydroxyphenylalanine (DOPA) in its own right, we attempted to clarify whether i.p. injection of a DOPA antagonist, DOPA cyclohexyl ester (CHE), would antagonize the behavioral responses of conscious rats to DOPA in the presence of 3-hydroxybenzylhydrazine (NSD-1015) (100 mg/kg i.p.), a central aromatic L-amino acid decarboxylase (AADC) inhibitor. DOPA-CHE (40, 60 and 100 mg/kg) elicited a dose-dependent partial antagonism against the increase in locomotor activity induced by DOPA (100 mg/kg i.p.). A low dose of DOPA-CHE (10 mg/kg) elicited full antagonism against the potentiating effect of a non-effective dose of DOPA (20 mg/kg) on the increase in locomotor activity induced by a dopamine D 2 agonist quinpirole (0.3 mg/kg s.c.). DOPA-CHE (100 mg/kg) elicited full antagonism against licking behavior induced by DOPA (100 mg/kg). We confirmed that DOPA (100 mg/kg) increased the striatal dopamine content but elicited no effect on locomotor activity in the presence of benserazide (50 mg/kg i.p.), a peripheral AADC inhibitor. DOPA also increased the dopamine content in the presence of NSD-1015 to a maximal degree similar to that in the presence of benserazide. Thus, we conclude that DOPA-CHE is a suitable DOPA antagonist that would be available under in vivo experimental conditions. DOPA plays a role in the neuromodulation of behavior.

L-3,4-Dihydroxyphenylalanine-induced c-Fos expression in the CNS under inhibition of central aromatic l-amino acid decarboxylase

l-3,4-Dihydroxyphenylalanine (DOPA) is a neurotransmitter candidate. To map the DOPAergic system functionally, DOPA-induced c-Fos expression was detected under inhibition of central aromatic l-amino acid decarboxylase (AADC). In rats treated with a central AADC inhibitor, DOPA significantly increased the number of c-Fos-positive nuclei in the paraventricular nuclei (PVN) and the nucleus tractus solitarii (NTS), and showed a tendency to increase in the supraoptic nuclei (SON), but not in the striatum. On the other hand, DOPA with a peripheral AADC inhibitor elevated the level of c-Fos-positive nuclei in the four regions, suggesting that DOPA itself induces c-Fos expression in the SON, PVN and NTS. In rats treated with 6-hydroxydopamine (6-OHDA) to lesion the nigrostriatal dopamine (DA) pathway, DOPA significantly induced c-Fos expression in the four regions under the inhibition of peripheral AADC. However, under the inhibition of central AADC, DOPA did not significantly increase the number of c-Fos-positive nuclei in the four regions, suggesting that DOPA at least in part induces c-Fos expression through its conversion to DA. It was likely that the 6-OHDA lesion enhanced the response to DA, but attenuated that to DOPA itself. In conclusion, we proposed that the SON, PVN and NTS include target sites for DOPA itself.

50. AAV-Mediated Expression and Secretion of ADNF-9 Protects Substantia Nigra Neurons from 6-OHDA Damage

Parkinson's disease (PD) is a progressive movement disorder marked by selective degeneration of dopaminergic neurons of the substantia nigra and severe decrease in the dopamine (DA) content of the striatum. Replacement of DA is important to alleviate the motor symptoms of the disease. The DA precursor, L-3,4-dihydroxyphenylalanine (L-dopa), which is converted to DA by aromatic L-amino acid decarboxylase (AADC), provides clinical benefit to virtually all patients and has been mainstay in pharmacotherapy for PD. However, as the disease progresses, severe loss of dopaminergic nerve terminals is associated with an 80–95% depletion of striatal AADC activity resulting in loss of L-dopa efficacy. We demonstrated previously that AAV vector-mediated gene transfer of three DA-synthesizing enzymes, namely tyrosine hydroxylase, AADC, and GTP cyclohydrolase I, resulted in behavioral recovery in animal models of PD with efficient and long-term transduction of striatal neurons. In the present experiments, we investigated the therapeutic potential of the combination therapy, gene transfer of AADC with oral administration of L-dopa, in a primate bilateral model of PD. Cynomolgus macaques (Macaca fascicularis) were chronically treated with 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) to make bilateral striatal lesions. Animals became behaviorally stable and motor symptoms did not ameliorate by the administration of L-dopa with peripheral AADC inhibitor. Then, adeno-associated virus (AAV) vector expressing AADC was injected into the unilateral putamen stereotaxically. Expression of AADC in the unilateral putamen resulted in remarkable improvement in manual dexterity on the contralateral to the AAV-AADC-injected side after the oral administration of L-dopa with peripheral AADC inhibitor. Fine motor task consists of capturing a piece of an apple improved on the contralateral hand with L-dopa. Amelioration of motor symptoms persisted about four hours each time after the oral intake of L-dopa. This duration of efficacy corresponds to the effective blood concentrations of the drug. Positron emission tomography showed remarkable and persistent increase of [11C]-L-dopa uptake in the AAV-AADC injected putamen. Gene transfer of AADC alone in combination with oral administration of L-dopa could be a shortcut to starting clinical trials of gene therapy for PD. With this method, patients still need to take L-dopa for the control of PD symptoms, but DA production can be regulated by the dose of L-dopa.

Effects of benserazide on L-DOPA-derived extracellular dopamine levels and aromatic L-amino acid decarboxylase activity in the striatum of 6-hydroxydopamine-lesioned rats.

Benserazide is commonly used for Parkinson's disease in combination with L-DOPA as a peripheral aromatic L-amino acid decarboxylase (AADC) inhibitor. However, recent studies using intact animals indicate that benserazide acts also in the central nervous system. We determined the influence of benserazide on the central AADC activity in rats with dopaminergic denervation and observed changes in extracellular dopamine (DA) levels after benserazide and L-DOPA administration. First, using in vivo microdialysis technique, we measured extracellular DA levels in the striatum of 6-hydroxydopamine (6-OHDA)-lesioned rats treated with benserazide and L-DOPA. Second, we measured AADC activity in the striatal tissues after benserazide administration. Although administration of 5, 10 and 50 mg/kg benserazide to 6-OHDA-lesioned rats showed an identical increase in exogenous L-DOPA-derived extracellular DA levels, the time to reach the peak DA levels were significantly prolonged by benserazide dose-dependently. The AADC activity in the denervated striatal tissues showed a significant decrease by 10 mg/kg and 50 mg/kg benserazide. These results suggest that benserazide reduces the central AADC activity in the striatum of rats with nigrostriatal denervation, which leads to changes in the metabolism of exogenous L-DOPA. Central activity of AADC inhibitors should be taken into consideration when they are used both in experimental and clinical studies on Parkinson's disease.

Variable absorption of carbidopa affects both peripheral and central levodopa metabolism.

Carbidopa (CD), a competitive inhibitor of aromatic l-amino acid decarboxylase that does not cross the blood-brain barrier, is routinely administered with levodopa (LD) to patients with Parkinson disease (PD) to reduce the peripheral decarboxylation of LD to dopamine. Using a stable isotope-labeled form of LD, the authors examined in 9 PD patients the effects of variable CD absorption on peripheral and central LD metabolism. Subjects were administered orally 50 mg of CD followed in 1 hour by a slow bolus intravenous infusion of 150 mg stable isotope-labeled LD (ring 1',2',3',4',5',6'-13C). Eight patients underwent a lumbar puncture 6 hours following the infusion. Blood and cerebrospinal fluid (CSF) samples were analyzed for labeled and unlabeled metabolites using a combination of high-performance liquid chromatography and mass spectrometry. When patients were divided into "slow" and "rapid" CD absorption groups, significantly greater peripheral LD decarboxylation (as measured by area under the curve [AUC]-labeled serum HVA) was noted in the poor absorbers (p = 0.05, Mann-Whitney U test). Elimination half-lives for serum LD did not differ between groups, suggesting a further capacity for decarboxylation inhibition in the "rapid" absorbers. A significant correlation between AUC serum CD and percent-labeled HVA in CSF was found for all patients (R = 0.786, p = 0.02). "Rapid" as compared to "slow" CD absorbers had significantly more percent-labeled CSF HVA (60 vs. 49, p = 0.02, Mann-Whitney U test), indicating greater central-labeled DA production in the better CD absorbers. The data suggest that peripheral aromatic l-amino acid decarboxylase activity is not saturated at CD doses used in current practice. The authors believe that future studies to better examine a dose dependence of CD on peripheral LD decarboxylation and LD brain uptake are warranted.

The antinatriuretic action of gamma‐L‐glutamyl‐5‐hydroxy‐L‐tryptophan is dependent on its decarboxylation to 5‐hydroxytryptamine in normal man.

1. The effects of inhibition of peripheral aromatic L-amino acid decarboxylase during infusion of the relatively renally selective 5-hydroxytryptamine (5-HT) prodrug, gamma-L-glutamyl-5-hydroxy-L-tryptophan (glu-5-HTP), were examined in eight healthy male subjects in a randomised, placebo-controlled, cross-over study. 2. Each subject received oral carbidopa (100 mg) or placebo followed, 1 h later, by a 60 min intravenous infusion of glu-5-HTP (16.6 micrograms kg-1 min-1) or placebo. 3. After administration of glu-5-HTP, cumulative urinary excretion of 5-HT was 430-fold greater than that after placebo, and was associated with a period of sodium retention. 4. Pretreatment with carbidopa substantially attenuated the increase in 5-HT excretion after glu-5-HTP and abolished its antinatriuretic effect. 5. These results are in keeping with the proposition that the antinatriuretic action of glu-5-HTP is dependent on its decarboxylation to 5-HT.

Differential effects of the novel antidepressant tianeptine on l-5-hydroxytryptophan (5-HTP)-elicited corticosterone release and body weight loss

Biochemical and behavioural experiments have indicated that the novel antidepressant tianeptine stimulates 5-hydroxytryptamine (5-HT) reuptake. The present study has explored the influence of acute tianeptine pretreatment upon corticosterone release and body weight loss following l-5-hydroxytryptophan (5-HTP) administration in conscious rats. Administration of 5-HTP (20 mg/kg i.v.) increased plasma corticosterone levels to a similar extent in rats pretreated either with saline or tianeptine (10 mg/kg i.p., 60 min beforehand). Besides, prior administration of benserazide (50 mg/kg i.p., 30 min beforehand), an inhibitor of peripheral aromatic l-amino acid decarboxylase, prevented 5-HTP-induced corticosterone release in both saline- and tianeptine-pretreated rats. However, combined administration of benserazidee and 5-HTP decreased overnight body weight in saline-, but not in tianeptine-pretreated rats. These results suggest that tianeptine preferentially activates 5-HT reuptake in central serotonergic neurones.

Central action of benserazide after COMT inhibition demonstrated in vivo by PET

Positron emission tomography (PET) following intravenous administration of beta-[11C]-L-DOPA provides a method of assessing regional cerebral uptake and utilization of levodopa. Cerebral levodopa kinetics in the rhesus monkey were investigated after the inhibition of catechol-O-methyltransferase (COMT) with RO 40-7592, and after coadministration of the peripheral aromatic L-amino acid decarboxylase (AADC) inhibitors benserazide and carbidopa. Pretreatment with RO 40-7592 (10 mg/kg), benserazide (10 mg/kg) or carbidopa (3.5 mg/kg) did not change striatal k3, which mainly reflects the ability for the brain tissue to convert [11C]-L-DOPA to [11 C]-dopamine, although the brain's uptake of radioactivity increased substantially after pretreatment with the AADC inhibitors. When benserazide was coadministered with RO 40-7592 (10 mg/kg) a dose-dependent decrease in striatal k3 was measured with an apparent ED50 of 3 mg/kg. No such effect was indicated after pretreatment with the combination of RO 40-7592 (10 mg/kg) and carbidopa (3.5 mg/kg). The possible negative interactions of coadministration with COMT inhibitors and predominantly peripherally acting AADC inhibitors must be considered when used in the therapy of Parkinson's disease.

Effect of L-threo-3,4-dihydroxyphenylserine (L-DOPS), an immediate precursor of norepinephrine, on the cerebral blood flow in rats.

L-threo-3,4-Dihydroxyphenylserine (L-DOPS), a norepinephrine (NE) precursor, 3 mg/kg, i.v., increased the cerebral blood flow (CBF) in both the striatum and hippocampus as well as the mean arterial blood pressure (MABP) in urethane-anesthetized rats, as NE infusion did. The L-DOPS induced increase in CBF was inhibited by benserazide (3 mg/kg/hour), a peripheral aromatic L-amino acid decarboxylase inhibitor, and propranolol (3 mg/kg, i.p.), a beta-adrenoceptor blocker as well. These results suggest that the effects of L-DOPS may be attributed to the action of NE formed from L-DOPS, and the action may be mediated by stimulation of beta-adrenoceptor.

Metoclopramide antagonism of 5-hydroxytryptophan-induced ?Wet-Dog? shake behaviour in the rat

1. Metoclopramide, a drug with blocking activity at peripheral neuronal receptor sites for 5-hydroxytryptamine (5-HT), was investigated as an antagonist of the ‘Wet-Dog’ shake response (WDS) to injections of 5-hydroxytryptophan (5-HTP) in rats. Its effects were compared with those of methysergide, an antagonist of 5-HT at non-neuronal receptor sites, and haloperidol, a dopamine receptor antagonist. 2. WDS after 5-HTP and carbidopa, an inhibitor of peripheral aromatic l-amino acid decarboxylase, correlates significantly with the increase in whole brain 5-HT concentrations measured in parallel experiments. 3. Metoclopramide, methysergide and haloperidol inhibited WDS. Metoclopramide, in addition, inhibited the increase in brain 5-HT, but not, apparently, by interfering with the decarboxylase enzyme. 4. Inhibition of the rise in brain 5-HT could not explain inhibition of WDS by metoclopramide, since metoclopramide inhibited 5-HTP-induced shaking once established and also the response to quipazine, a directly-acting agonist at central 5-HT receptors. 5. The mechanism of action of methysergide may involve blockade of post-synaptic receptor sites for 5-HT. Metoclopramide and haloperidol, on the other hand, cause catalepsy at doses which inhibit WDS, presumably through blockade of dopamine receptors in the CNS. The consequent inhibition of the ability of the animals to initiate movement may be the mechanism by which these compounds inhibit WDS. 6. Since agents with cataleptic properties, probably unconnected to brain 5-HT mechanisms, are effective antagonists of the shaking response, WDS after 5-HTP may be less useful than previously supposed as a screen for durgs interacting with 5-HT receptors in the CNS.

L-3,4-dihydroxyphenylalanine (L-dopa) as an inhibitor of prolactin release.

A series of experiments was performed on estrogen/progesterone-treated, ovariectomized rats to determine the site of the inhibitory effect of L-3,4- dihydroxyphenylalanine (L-dopa) on prolactin release. After intraarterial injection of L-[3H]dopa (150 μCi), [3H]norepinephrine ([3H]NE), [3H]dopamine ([3H]DA), and L-[3H]dopa were found in the hypothalamus and anterior pituitary. Intra-arterial injection of L-dopa (2, 5, or 10 mg/kg) produced a dose-related inhibition of prolactin release. The magnitude and the duration of inhibition of prolactin release were greater with increasing doses of L-dopa. Hypothalamic concentrations of endogenous DA were significantly increased 30 min after L-dopa (10 mg/kg) and were correlated with decreased serum prolactin levels at this time. Hypothalamic NE content was not affected. L-α-Methyldopa hydrazine, 20 mg/kg (Mk 486), a peripheral aromatic L-amino acid decarboxylase inhibitor, injected 30 min before L-[3H]dopa injection, increased the concentration of L-[3H]dopa in th...

Possible mechanism of adverse reaction following levodopa plus benserazide treatment.

1 Rats treated for seven days with seryl-trihydroxybenzylhydrazine (benserazide), and inhibitor of peripheral aromatic L-amino acid decarboxylase (500 mg/kg, daily, i.p.) alone or in combination with L-DOPA methylester (500 mg/kg, daily, i.p.) for seven days showed a moderate but significant decrease of liver aldehyde dehydrogenase (ALDH), without accompanying change in alcohol dehydrogenase (ADH) activity, compared with saline-treated controls. 2 Administration of L-DOPA methylester (500 mg/kg, daily, i.p.) alone for seven days had little effect on liver ADH or ALDH. 3. The combined treatment might be conducive to the in vivo formation of L-DOPA-derived tetrahydroisoquinoline derivatives which might be implicated in L-DOPA produced adverse effects.

Interactions Between Levodopa and Other Drugs

Levodopa (L-3,4 dihydroxyphenylalanine), an amino acid which is currently the most useful drug for the management of Parkinson’s disease is an excellent case in point for an important generality concerning drug treatment: Since the responses of individual patients to a specific drug may be remarkably diverse, careful individualisation of total management of the treatment is necessary in order to maximise its therapeutic effects. Relevant variables in individual response effects include the natural history of the disease under treatment, associated illnesses, drug interactions, adverse effects of other drugs, idiosyncratic reactions and diet. This article considers, many of the factors which may alter either the therapeutic efficacy or the adverse effects of levodopa in Parkinsonism or in related disorders. Levodopa absorption occurs mainly in the small intestine. The drug can be locally metabolised by decarboxylase at the gastric mucosa. High protein diet and prolonged gastric emptying time may negate the therapeutic efficacy of levodopa. Among the many inhibitors of enzyme processes important to catecholamine metabolism, only peripheral aromatic L-amino acid decarboxylase inhibitors appear to have clinical importance at present. Pyridoxine (Vitamin B6) may rapidly minimise or negate the effects of levodopa in Parkinsonism by enhancing its extracerebral metabolism. Concomitant administration of monoamine oxidase inhibitors and levodopa may cause severe hypertensive crisis. Since this phenomenon is not uniform or predictable, the effect of monoamine oxidase inhibitors in slowing degradation of cerebral dopamine cannot be utilised clinically to lower the dosage requirement of levodopa. It is well recognised that selected anticholinergic drugs have modest antiparkinsonian effects. However, in certain parkinsonian patients, these drugs will markedly delay gastric emptying and thus perhaps minimise or negate the therapeutic benefit from levodopa. Reserpine, phenothiazines, butyrophenones and tetrabenazine all may alter the function of dopaminergic pathways and hence may significantly interfere with the therapeutic efficacy of levodopa.